In immune reactions in the body, cytokines produced from various immunocytes control direction of the immune responses. In this regulation of immune responses, it is helper T cells that play a central role, and they are classified into subsets Th1 and Th2 depending upon the type of cytokines they produce. Th1 type cells are known to produce mainly e.g. interleukin 2 (IL-2) and interferon γ (IFN-γ) and to be concerned with cellular immunity such as protection of infection against e.g. virus and bacteria. Th2 type cells are known to produce mainly e.g. interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 6 (IL-6), interleukin 10 (IL-10) and interleukin 13 (IL-13) and to be concerned with humoral immunity such as protection of infection against parasites and antibody production from B cells. However, it has been clarified that if control of such biophylactic mechanism dysfunctions or deteriorates for some reason, hyperactivation or imbalance of immune function may occur, thus inducing or deteriorating various diseases.
Immune response of Th2 type induces or activates, due to its hyperactivation, allergic inflammation reactions such as immediate type allergy with which IgE antibody or mast cells are mainly concerned, and delayed-type allergy with which eosinophils are mainly concerned, and is deeply concerned with induction or deterioration of various allergic diseases such as urticaria, food allergy, anaphylactic shock, hypereosinophilic syndrome, asthma, allergic rhinitis, allergic conjunctivitis and atopic dermatitis. Further, abnormal hyperactivation of immune reaction of Th2 type is deeply concerned also with systemic autoimmune diseases in a pathophysiologic state where antibody production or humoral immunity is hyperactivated, such as systemic lupus erythematosus. It is considered to be important to control the immune response of Th2 type in order to treat or prevent such allergic diseases. On the other hand, immune response of Th1 type induces or activates cellular immune responses due to its hyperactivation, and is deeply concerned with induction or deterioration of organ specific autoimmune diseases such as chronic rheumatoid arthritis, type I diabetes, Hashimoto's thyroiditis, myasthenia gravis and multiple sclerosis. Further, cellular immune response of Th1 type is deeply concerned also with graft rejection accompanying organ transplantation. It is considered to be important to control immune response of Th1 type in order to prevent or treat such autoimmune diseases or graft rejection after transplantation.
As compounds which are analogous in chemical structures to the aniline derivative or a salt thereof as an active ingredient of the cytokine production inhibitors of the present invention, compounds as disclosed in WO95/146, WO98/27081, WO98/27058, WO99/15164, WO99/51580 and WO00/40235 may, for example, be mentioned. However, such compounds and the compounds of the present invention are different in their chemical structures.
At the present time, it is difficult to treat such serious immune or allergic diseases by specifically regulating immune response of Th1 or Th2 type, and immunosuppressant agents which strongly suppress production of both Th1 and Th2 type cytokines, such as cyclosporin and FK506, in addition to steroids, are mainly used as therapeutic medicines for such diseases. However, various side effects such as dysfunction of adrenal cortex, diabetes, peptic ulcer and glaucoma have been problematic with respect to steroids, and serious side effects such as damages in kidney and central nervous system have been problematic with respect to cyclosporin and FK506, and development of a new type of cytokine production inhibitors which are different from the above agents, has been desired.